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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1265-1273. Prepublished online as a Blood First Edition Paper on September 23, 2004; DOI 10.1182/blood-2004-03-0964. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0964v1 105/3/1265    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Evens, A. M. Articles by Gordon, L. I. Search for Related Content PubMed PubMed Citation Articles by Evens, A. M. Articles by Gordon, L. I. Related Collections Neoplasia Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells Andrew M. Evens, Philip Lecane, Darren Magda, Sheila Prachand, Seema Singhal, Jeff Nelson, Richard A. Miller, Ronald B. Gartenhaus, and Leo I. Gordon From the Division of Hematology/Oncology, Department of Medicine, Department of Pathology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; and Pharmacyclics, Inc, Sunnyvale, CA. Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production, and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414) chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells. We found complete inhibition of proliferation and cytotoxicity in each sensitive and resistant cell line with 24-hour exposure to clinically relevant concentrations of 50 µM MGd and 50 to 100 µM ascorbate, which was required for the effect. The mechanism of cytotoxicity was related to induction of apoptosis as demonstrated by alteration in mitochondrial membrane potential and elevated annexin V expression. This was accompanied by depletion of intracellular glutathione and increased ROS production. Moreover, catalase substantially abrogated MGd-induced cell death. Using fluorescence microscopy and flow cytometry, we found intracellular uptake of MGd and intracellular ROS production. MGd also induced apoptosis in fresh malignant cells from patients with multiple myeloma. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Evens, W. G. Spies, I. B. Helenowski, D. Patton, S. Spies, B. D. Jovanovic, S. Miyata, E. Hamilton, D. Variakojis, J. Chen, et al. The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with [90Y]Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin's Lymphoma: Preclinical Findings and Results of a Phase I Trial Clin. Cancer Res., October 15, 2009; 15(20): 6462 - 6471. [Abstract] [Full Text] [PDF] S. Bhalla, S. Balasubramanian, K. David, M. Sirisawad, J. Buggy, L. Mauro, S. Prachand, R. Miller, L. I. Gordon, and A. M. Evens PCI-24781 Induces Caspase and Reactive Oxygen Species-Dependent Apoptosis Through NF-{kappa}B Mechanisms and Is Synergistic with Bortezomib in Lymphoma Cells Clin. Cancer Res., May 15, 2009; 15(10): 3354 - 3365. [Abstract] [Full Text] [PDF] T. Dragovich, M. Gordon, D. Mendelson, L. Wong, M. Modiano, H.-H. S. Chow, B. Samulitis, S. O'Day, K. Grenier, E. Hersh, et al. Phase I Trial of Imexon in Patients With Advanced Malignancy J. Clin. Oncol., May 1, 2007; 25(13): 1779 - 1784. [Abstract] [Full Text] [PDF] C. R. Isham, J. D. Tibodeau, W. Jin, R. Xu, M. M. Timm, and K. C. Bible Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress Blood, March 15, 2007; 109(6): 2579 - 2588. [Abstract] [Full Text] [PDF] J. P. Evans, F. Xu, M. Sirisawad, R. Miller, L. Naumovski, and P. R. O. de Montellano Motexafin Gadolinium-Induced Cell Death Correlates with Heme oxygenase-1 Expression and Inhibition of P450 Reductase-Dependent Activities Mol. Pharmacol., January 1, 2007; 71(1): 193 - 200. [Abstract] [Full Text] [PDF] S. I. Hashemy, J. S. Ungerstedt, F. Z. Avval, and A. Holmgren Motexafin Gadolinium, a Tumor-selective Drug Targeting Thioredoxin Reductase and Ribonucleotide Reductase J. Biol. Chem., April 21, 2006; 281(16): 10691 - 10697. [Abstract] [Full Text] [PDF] L. Yu, F. Wan, S. Dutta, S. Welsh, Z. Liu, E. Freundt, E. H. Baehrecke, and M. Lenardo Autophagic programmed cell death by selective catalase degradation PNAS, March 28, 2006; 103(13): 4952 - 4957. [Abstract] [Full Text] [PDF] P. S. Lecane, M. W. Karaman, M. Sirisawad, L. Naumovski, R. A. Miller, J. G. Hacia, and D. Magda Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines Cancer Res., December 15, 2005; 65(24): 11676 - 11688. 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